The assertive community treatment team: an appropriate treatment for medical disorders that present with prominent psychiatric symptoms.

Physical diseases are difficult to treat in psychiatric patients, whether they are comorbid disorders or mental disorders due to a general medical condition. The psychiatric symptoms are difficult to treat in a medical ward or clinic, and the physical symptoms are difficult to treat in a psychiatric ward or clinic. For this reason, medical-psychiatric units have been developed but remain uncommon. It has been suggested that assertive community treatment (ACT) teams are a way in which to integrate medical and psychiatric treatments. We review the case of a woman with psychiatric symptoms caused by Graves disease that went untreated due to medication noncompliance and unmanageable irritability, aggression, and mood variability. We make a case for the use of the assertive community treatment team in the treatment of patients with mental disorders due to a general medical condition when the psychiatric manifestations are severe and cannot be managed in a medical ward or clinic.

Factors associated with trauma clinic follow-up compliance after discharge: experience at an urban Level I trauma center.

BACKGROUND: Disparities in access to postdischarge services for trauma patients exist, and clinic follow-up remains an important avenue to ensure initial and continued access to postdischarge services. In addition, follow-up is vital to rigorous long-term trauma outcomes research. However, there is a relative paucity of literature specifically addressing clinic follow-up. The purposes of this study were to elucidate factors associated with clinic follow-up compliance and noncompliance after discharge from an urban Level I trauma center and to confirm the prevailing notion that follow-up in trauma clinic is poor. METHODS: Our trauma registry was queried for all trauma service discharges of patients 18 years and older for a 2-year period. Patients with incomplete information were excluded. Demographic data such as race/ethnicity and insurance status were collected on all patients. Primary outcome was defined as trauma clinic follow-up within 4 weeks after discharge. Patients compliant with follow-up were compared with noncompliant patients. RESULTS: After exclusion criteria were applied, there were 1,818 discharges included in the analysis, with 564 (31%) complying with follow-up (p < 0.001). Factors significantly associated with follow-up noncompliance included patients older than 35 years, white race, Medicaid/Medicare payers, blunt mechanism, extended hospital length of stay, and discharge to rehabilitation facilities. No insurance, penetrating mechanism, short hospital stay, discharge to home, and weekend discharge were all significantly associated with follow-up compliance. Discharge on weekends and to home were independent predictors of compliance, whereas, Medicaid/Medicare insurance status and operative intervention were independent predictors of noncompliance. CONCLUSION: This study indentifies factors associated with trauma clinic follow-up compliance and confirms the notion that trauma clinic follow-up compliance at an urban Level I trauma center is alarmingly low. These findings may serve as targets to improve follow-up, thereby improving trauma outcomes research and long-term outcomes. Consequently, clinic follow-up compliance warrants further study and consideration as an essential trauma registry datum. LEVEL OF EVIDENCE: Prognostic study, level III.

Is the restricted ketogenic diet a viable alternative to the standard of care for managing malignant brain cancer?

Malignant brain cancer persists as a major disease of morbidity and mortality. The failure to recognize brain cancer as a disease of energy metabolism has contributed in large part to the failure in management. As long as brain tumor cells have access to glucose and glutamine, the disease will progress. The current standard of care provides brain tumors with access to glucose and glutamine. The high fat low carbohydrate ketogenic diet (KD) will target glucose availability and possibly that of glutamine when administered in carefully restricted amounts to reduce total caloric intake and circulating levels of glucose. The restricted KD (RKD) targets major signaling pathways associated with glucose and glutamine metabolism including the IGF-1/PI3K/Akt/Hif pathway. The RKD is anti-angiogenic, anti-invasive, anti-inflammatory, and pro-apoptotic when evaluated in mice with malignant brain cancer. The therapeutic efficacy of the restricted KD can be enhanced when combined with drugs that also target glucose and glutamine. Therapeutic efficacy of the RKD was also seen against malignant gliomas in human case reports. Hence, the RKD can be an effective non-toxic therapeutic option to the current standard of care for inhibiting the growth and invasive properties of malignant brain cancer.

Influence of caloric restriction on constitutive expression of NF-κB in an experimental mouse astrocytoma.

BACKGROUND: Many of the current standard therapies employed for the management of primary malignant brain cancers are largely viewed as palliative, ultimately because these conventional strategies have been shown, in many instances, to decrease patient quality of life while only offering a modest increase in the length of survival. We propose that caloric restriction (CR) is an alternative metabolic therapy for brain cancer management that will not only improve survival but also reduce the morbidity associated with disease. Although we have shown that CR manages tumor growth and improves survival through multiple molecular and biochemical mechanisms, little information is known about the role that CR plays in modulating inflammation in brain tumor tissue. METHODOLOGY/PRINCIPAL FINDINGS: Phosphorylation and activation of nuclear factor κB (NF-κB) results in the transactivation of many genes including those encoding cycloxygenase-2 (COX-2) and allograft inflammatory factor-1 (AIF-1), both of which are proteins that are primarily expressed by inflammatory and malignant cancer cells. COX-2 has been shown to enhance inflammation and promote tumor cell survival in both in vitro and in vivo studies. In the current report, we demonstrate that the p65 subunit of NF-κB was expressed constitutively in the CT-2A tumor compared with contra-lateral normal brain tissue, and we also show that CR reduces (i) the phosphorylation and degree of transcriptional activation of the NF-κB-dependent genes COX-2 and AIF-1 in tumor tissue, as well as (ii) the expression of proinflammatory markers lying downstream of NF-κB in the CT-2A malignant mouse astrocytoma, [e.g. macrophage inflammatory protein-2 (MIP-2)]. On the whole, our date indicate that the NF-κB inflammatory pathway is constitutively activated in the CT-2A astrocytoma and that CR targets this pathway and inflammation. CONCLUSION: CR could be effective in reducing malignant brain tumor growth in part by inhibiting inflammation in the primary brain tumor.

Metabolic management of brain cancer.

Malignant brain tumors are a significant health problem in children and adults. Conventional therapeutic approaches have been largely unsuccessful in providing long-term management. As primarily a metabolic disease, malignant brain cancer can be managed through changes in metabolic environment. In contrast to normal neurons and glia, which readily transition to ketone bodies (ß-hydroxybutyrate) for energy under reduced glucose, malignant brain tumors are strongly dependent on glycolysis for energy. The transition from glucose to ketone bodies as a major energy source is an evolutionary conserved adaptation to food deprivation that permits the survival of normal cells during extreme shifts in nutritional environment. Only those cells with a flexible genome and normal mitochondria can effectively transition from one energy state to another. Mutations restrict genomic and metabolic flexibility thus making tumor cells more vulnerable to energy stress than normal cells. We propose an alternative approach to brain cancer management that exploits the metabolic flexibility of normal cells at the expense of the genetically defective and metabolically challenged tumor cells. This approach to brain cancer management is supported from recent studies in mice and humans treated with calorie restriction and the ketogenic diet. Issues of implementation and use protocols are presented for the metabolic management of brain cancer.

Targeting energy metabolism in brain cancer through calorie restriction and the ketogenic diet.

Malignant brain tumors are a significant health problem in children and adults and are largely unmanageable. As a metabolic disorder involving the dysregulation of glycolysis and respiration (the Warburg effect), malignant brain cancer can be managed through changes in metabolic environment. In contrast to malignant brain tumors that are mostly dependent on glycolysis for energy, normal neurons and glia readily transition to ketone bodies (beta-hydroxybutyrate) for energy in vivo when glucose levels are reduced. The transition from glucose to ketone bodies as a major energy source is an evolutionary conserved adaptation to food deprivation that permits the survival of normal cells during extreme shifts in nutritional environment. Only those cells with a flexible genome, honed through millions of years of environmental forcing and variability selection, can transition from one energy state to another. We propose a different approach to brain cancer management that exploits the metabolic flexibility of normal cells at the expense of the genetically defective and less metabolically flexible tumor cells. This approach to brain cancer management is supported from recent studies in orthotopic mouse brain tumor models and in human pediatric astrocytoma treated with calorie restriction and the ketogenic diet. Issues of implementation and use protocols are discussed.

Improvement in motor and exploratory behavior in Rett syndrome mice with restricted ketogenic and standard diets.

Rett syndrome (RTT) is a rare X-linked autistic-spectrum neurological disorder associated with impaired energy metabolism, seizure susceptibility, progressive social behavioral regression, and motor impairment primarily in young girls. The objective of this study was to examine the influence of restricted diets, including a ketogenic diet (KD) and a standard rodent chow diet (SD), on behavior in male Mecp2(308/y) mice, a model of RTT. The KD is a high-fat, low-carbohydrate diet that has anticonvulsant efficacy in children with intractable epilepsy and may be therapeutic in children with RTT. Following an 11-day pretrial period, adult wild-type and mutant Rett mice were separated into groups that were fed either an SD in unrestricted or restricted amounts or a ketogenic diet (KetoCal) in restricted amounts for a total of 30 days. The restricted diets were administered to reduce mouse body weight by 20-23% compared to the body weight of each mouse before the initiation of the diet. All mice were subjected to a battery of behavioral tests to determine the influence of the diet on the RTT phenotype. We found that performance in tests of motor behavior and anxiety was significantly worse in male RTT mice compared to wild-type mice and that restriction of either the KD or the SD improved motor behavior and reduced anxiety. We conclude that although both restricted diets increased the tendency of Rett mice to explore a novel environment, the beneficial effects of the KD were due more to calorie restriction than to the composition of the diet. Our findings suggest that calorically restricted diets could be effective in reducing the anxiety and in improving motor behavior in girls with RTT.

Akt-dependent proapoptotic effects of dietary restriction on late-stage management of a phosphatase and tensin homologue/tuberous sclerosis complex 2-deficient mouse astrocytoma.

PURPOSE: Malignant astrocytomas exhibit constitutive Akt phosphorylation due to reduced phosphatase and tensin homologue (PTEN) tumor suppressor expression or to increased growth factor receptor tyrosine kinase activation. Many astrocytomas are also tuberous sclerosis complex 2 (TSC2) protein deficient and exhibit constitutive mammalian target of rapamycin (mTOR) activity. Astrocytomas harboring PTEN/Akt/TSC2 pathway mutations are dependent on glycolysis to satisfy their bioenergetic requirements. Therapies that disrupt energy homeostasis can potentially manage astrocytoma growth and progression. Although dietary restriction (DR) reduces glycolysis and manages early-stage astrocytoma growth, no prior studies have identified the mechanisms involved or determined if DR can also manage late-stage tumor growth. EXPERIMENTAL DESIGN: The effects of a late-onset intermittent DR feeding paradigm were examined in adult C57BL/6J mice bearing the syngeneic CT-2A malignant astrocytoma grown orthotopically or subcutaneously. RESULTS: In contrast to contralateral normal brain, CT-2A was PTEN/TSC2 protein deficient; exhibited constitutive Akt, mTOR, and BAD phosphorylation; and overexpressed insulin-like growth factor-I (IGF-I), IGF-I receptor, hypoxia-inducible transcription factor-1alpha (HIF-1alpha), type 1 glucose transporter protein (GLUT1), and pyruvate kinase. DR initiated 10 to 14 days after tumor implantation (late onset) reduced CT-2A growth, delayed malignant progression, and significantly extended survival. DR suppressed phosphorylation of Akt and BAD while reducing expression of IGF-I, HIF-1alpha, and GLUT1. DR also enhanced procaspase-9/procaspase-3 cleavage but had no effect mTOR phosphorylation. CONCLUSIONS: Our findings indicate that IGF-I/Akt signaling is associated with the antiapoptotic and glycolytic phenotype of the CT-2A astrocytoma and that DR targets this pathway. Moreover, PTEN/TSC2 deficiency may impair adaptation to the DR-induced disruption of energy homeostasis, thus enhancing apoptosis. Our findings highlight the efficacy of late-onset DR in managing astrocytoma growth and suggest that DR may be an effective broad-spectrum inhibitor of Akt signaling in PTEN/TSC2-deficient astrocytomas.

Targeting energy metabolism in brain cancer with calorically restricted ketogenic diets.

Information is presented on the calorically restricted ketogenic diet (CRKD) as an alternative therapy for brain cancer. In contrast to normal neurons and glia, which evolved to metabolize ketone bodies as an alternative fuel to glucose under energy-restricted conditions, brain tumor cells are largely glycolytic due to mitochondrial defects and have a reduced ability to metabolize ketone bodies. The CRKD is effective in managing brain tumor growth in animal models and in patients, and appears to act through antiangiogenic, anti-inflammatory, and proapoptotic mechanisms.

Drug/diet synergy for managing malignant astrocytoma in mice: 2-deoxy-D-glucose and the restricted ketogenic diet.

BACKGROUND: Astrocytomas are largely dependent on glycolysis to satisfy their bioenergetic requirements for growth and survival. Therapies that target glycolysis can potentially manage astrocytoma growth and progression. Dietary restriction of the high fat/low carbohydrate ketogenic diet (KD-R) reduces glycolysis and is effective in managing experimental mouse and human astrocytomas. The non-metabolizable glucose analogue, 2-deoxy-D-glucose (2-DG), is a potent glycolytic inhibitor that can mimic effects of energy restriction both in vitro and in vivo, but can also produce adverse effects when administered at doses greater than 200 mg/kg. The goal here was to determine if low doses of 2-DG could act synergistically with the KD-R to better manage growth of the CT-2A malignant mouse astrocytoma. METHODS: The therapeutic effect of a KD-R supplemented with a low dose of 2-DG (25 mg/kg) was examined in adult C57BL/6J mice bearing the syngeneic CT-2A malignant astrocytoma grown orthotopically. Mice were fed the standard unrestricted diet for the first 3 days after tumor implantation prior to their separation into one of four diet groups fed either a standard rodent diet in unrestricted amounts (SD-UR) or a KD-R with or without 2-DG for 10 days. The KD-R was restricted to reduce body weight by about 20%. 2-DG was initiated 6 days after tumor implantation and was continued for 7 days. Brain tumors were excised and weighed. RESULTS: Energy intake, body weights, and CT-2A tumor weights were similar in the SD-UR and the SD-UR+2-2DG mouse groups over the dietary treatment period (days 3-13). Tumor weights were about 48% and 80% lower in the KD-R and in the KD-R+2-DG groups, respectively, than in the SD-UR group. Mouse health and vitality was better in the KD-R group than in the KD-R+2-DG group. CONCLUSION: Astrocytoma growth was reduced more in the KD-R mouse group supplemented with 2-DG than in the mouse groups receiving either dietary restriction or 2-DG alone, indicating a synergistic interaction between the drug and the diet. The results suggest that management of malignant astrocytoma with restricted ketogenic diets could be enhanced when combined with drugs that inhibit glycolysis.

Differential effects of energy stress on AMPK phosphorylation and apoptosis in experimental brain tumor and normal brain.

BACKGROUND: AMP-activated protein kinase (AMPK) is a known physiological cellular energy sensor and becomes phosphorylated at Thr-172 in response to changes in cellular ATP levels. Activated AMPK acts as either an inducer or suppressor of apoptosis depending on the severity of energy stress and the presence or absence of certain functional tumor suppressor genes. RESULTS: Here we show that energy stress differentially affects AMPK phosphorylation and cell-death in brain tumor tissue and in tissue from contra-lateral normal brain. We compared TSC2 deficient CT-2A mouse astrocytoma cells with syngeneic normal astrocytes that were grown under identical condition in vitro. Energy stress induced by glucose withdrawal or addition of 2-deoxyglucose caused more ATP depletion, AMPK phosphorylation and apoptosis in CT-2A cells than in the normal astrocytes. Under normal energy conditions pharmacological stimulation of AMPK caused apoptosis in CT-2A cells but not in astrocytes. TSC2 siRNA treated astrocytes are hypersensitive to apoptosis induced by energy stress compared to control cells. AMPK phosphorylation and apoptosis were also greater in the CT-2A tumor tissue than in the normal brain tissue following implementation of dietary energy restriction. Inefficient mTOR and TSC2 signaling, downstream of AMPK, is responsible for CT-2A cell-death, while functional LKB1 may protect normal brain cells under energy stress. CONCLUSION: Together these data demonstrates that AMPK phosphorylation induces apoptosis in mouse astrocytoma but may protect normal brain cells from apoptosis under similar energy stress condition. Therefore, using activator of AMPK along with glycolysis inhibitor could be a potential therapeutic approach for TSC2 deficient human malignant astrocytoma.

Targeted short-term fluconazole prophylaxis among very low birth weight and extremely low birth weight infants.

OBJECTIVES: To assess whether targeted short-term fluconazole prophylaxis reduces late-onset (>3 days of age) invasive fungal infection (IFI) among very low birth weight infants and extremely low birth weight (ELBW) infants and to assess mortality rates, toxicity, and costs associated with this intervention. METHODS: An observational study of 2 subsequent epochs of inborn infants with birth weight of <1500 g or gestational age of <32 weeks, 1 before (control) and 1 after (fluconazole) initiation of routine targeted fluconazole prophylaxis in March 2003, was performed. Targeted fluconazole (3 mg/kg) prophylaxis was administered to infants for whom a decision was made to administer broad-spectrum antibiotics for >3 days. RESULTS: IFI was observed for 13 (6.3%) of 206 infants in the control epoch and 2 (1.1%) of 178 in the fluconazole epoch, with a common odds ratio of 0.166. Logistic regression analysis taking into account all published factors (except for fungal colonization) showed that the fluconazole epoch was associated significantly with lower IFI rates. We observed no change in late (>3 days) mortality rates (11 of 206 infants in the control epoch vs 8 of 178 infants in the prophylaxis epoch). The mortality rate for ELBW infants with IFI was low (15%) in our study. Fluconazole was administered to 81% of ELBW infants, who received a median of 8 doses, and 41% of larger infants, who received a median of 5 doses. The intervention was cost-effective, and the effective number needed to treat to prevent 1 IFI was 10. CONCLUSIONS: This study suggests that targeted short-course fluconazole prophylaxis in very low birth weight and ELBW infants may be efficacious and cost effective.